Acquired immune deficiency syndrome ("AIDS") is a disease characterized by severe or, typically, complete immunosuppression and attendant host susceptibility to a wide range of opportunistic infections and malignancies. AIDS' complete clinical manifestation is usually preceded by AIDS related complex ("ARCS"), a syndrome accompanied by symptoms such as lymphadenopathy, fever and weight loss.
The human immunodeficiency virus ("HIV") retrovirus is thought to be the etiological agent responsible for AIDS infection and the ARCS syndrome [M. G. Sarngadharan et al., "Detection, Isolation, and Continuous Production of Cytopathic Retroviruses (HTLV-III) From Patients With AIDS and Pre-AIDS", Science, 224, pp. 497-508 (1984)].* Between 85 and 100% of the AIDS/ARCS patient population test seropositive for HIV [G. N. Shaw et al., "Molecular Characterization of Human T-Cell Leukemia (Lymphotropic) Virus Type III In The Acquired Immune Deficiency Syndrome", Science, 226, pp. 1165-1170 (1984)]. FNT * In this application, human immunodeficiency virus ("HIV"), the generic term adopted by the human retrovirus subcommittee of the International Committee on Taxonomy of Viruses to refer to independent isolates from AIDS patients, including human T-cell lymphotropic virus type III ("HTLV-III"), lymphadenopathy-associated virus ("LAV") and AIDS-associated retrovirus ("ARV") will be used.
Upon infection of a host, the primary targets of the HIV virus are T-4 lymphocytes, also known as helper or inducer cells. T-4 lymphocytes interact with other specialized cell types of the immune system to confer immunity to or defense against infection. More specifically, T-4 lymphocytes stimulate production of growth factors which are critical to the functioning of the immune system. For example, they act to stimulate B cells, the descendants of hemopoietic stem cells, which promote the production of defensive antibodies. They also activate macrophages ("killer cells") to attack infected or otherwise abnormal host cells, and induce monocytes ("scavenger cells") to encompass and destroy invading microbes. Accordingly, when T-4 lymphocytes are rendered non-functional by HIV infection, this complex immune defense system is destroyed and the host becomes susceptible to a wide range of opportunistic infections. In addition to T-4 lymphocytes, the HIV virus has also been shown to infect central nervous system cells, macrophages and B lymphocytes [J. M. Ismach, "AIDS: Can The Nation Cope", Medical World News (Aug. 25, 1985)].
The genome of retroviruses such as HIV contains three regions encoding structural proteins. The gag region encodes the core proteins of the virion. The pol region encodes the virion RNA-dependent DNA polymerase (reverse transcriptase). The env region encodes the major glycoprotein found in the membrane envelope of the virus and in the cytoplasmic membrane of infected cells. The capacity of the virus to attach to target cell receptors and to cause fusion of cell membranes are two HIV virus properties controlled by the env gene. These properties are believed to play a fundamental role in the pathogenesis of the virus.
HIV env proteins arise from a precursor polypeptide that, in mature form, is cleaved into a large heavily glycosylated exterior membrane protein of about 481 amino acids--gp120--and a smaller transmembrane protein of about 345 amino acids which may be glycosylated--gp41 [L. Ratner et al., "Complete Nucleotide Sequence Of The Aids Virus, HTLV-III", Nature, 313, pp. 277-284 (1985).
In the absence to date of effective treatments for AIDS, many efforts have centered on prevention of the disease. Such preventative measures include HIV antibody screening of all blood, organ and semen donors and education of AIDS high-risk groups regarding transmission of the disease.
Experimental or early-stage clinical treatment of AIDS and ARCS conditions have included the administration of antiviral drugs, such as HPA-23, phosphonoformate, suramin and ansamycin, which apparently interfere with replication of the virus by inhibiting its reverse transcriptase. Administration of some of these drugs in effective amounts has, however, been accompanied by undesirable and debilitating side effects. Other proposed methods for treating AIDS have focused the administration of alpha interferon or the application of hybridoma technology. Most of these treatment strategies are expected to require the co-administration of immunomodulators, such as interleukin-2. However, while some of these treatments are promising, none has been shown to be truly effective.
Recent studies have also demonstrated that HIV is experiencing genetic drift in humans. At least two classes of the virus have now been identified in AIDS patients in the United States. Furthermore, patients having high levels of HIV neutralizing antibodies suffer more serious forms of the disease than those patients with poor neutralizing capabilities [Dr. William Haseltine, speech at Memorial Sloan-Kettering Cancer Center, Oct. 9, 1985]. These recent observations suggest serious obstacles to the development of an effective vaccine or monoclonal antibody-directed therapeutic method against HIV AIDS infections.
Accordingly, despite these developments to date, the need exists for the development of effective agents for the prevention, treatment and diagnosis of HIV and AIDS-related infections.